CD34 explained

CD34 is a transmembrane phosphoglycoprotein protein encoded by the CD34 gene in humans, mice, rats and other species.^{[1] [2] [3]}

CD34 derives its name from the cluster of differentiation protocol that identifies cell surface antigens. CD34 was first described on hematopoietic stem cells independently by Civin et al. and Tindle et al.^{[4] [5] [6] [7]} as a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of hematopoietic stem cells to bone marrow extracellular matrix or directly to stromal cells. Clinically, it is associated with the selection and enrichment of hematopoietic stem cells for bone marrow transplants. Due to these historical and clinical associations, CD34 expression is almost ubiquitously related to hematopoietic cells; however, it is actually found on many other cell types as well.

Function

The CD34 protein is a member of a family of single-pass transmembrane sialomucin proteins that show expression on early haematopoietic and vascular-associated progenitor cells.^[8] However, little is known about its exact function.^[9]

CD34 is also an important adhesion molecule and is required for T cells to enter lymph nodes. It is expressed on lymph node endothelia, whereas the L-selectin to which it binds is on the T cell.^{[10] [11]} Conversely, under other circumstances CD34 has been shown to act as molecular "Teflon" and block mast cell, eosinophil and dendritic cell precursor adhesion, and to facilitate opening of vascular lumina.^{[12] [13]} Finally, recent data suggest CD34 may also play a more selective role in chemokine-dependent migration of eosinophils and dendritic cell precursors.^{[14] [15]} Regardless of its mode of action, under all circumstances CD34, and its relatives podocalyxin and endoglycan, facilitates cell migration.^[8]

Tissue distribution

Cells expressing CD34 (CD34⁺ cell) are normally found in the umbilical cord and bone marrow as haematopoietic cells, or in endothelial progenitor cells, endothelial cells of blood vessels but not lymphatics (except pleural lymphatics), mast cells, a sub-population of dendritic cells (which are factor XIIIa-negative) in the interstitium and around the adnexa of dermis of skin, as well as cells in soft tissue tumors like DFSP, GIST, SFT, HPC, and to some degree in MPNSTs, etc. The presence of CD34 on non-hematopoietic cells in various tissues has been linked to progenitor and adult stem cell phenotypes.^[16]

It is important to mention that Long-Term Haematopoietic Stem Cells (LT-HSCs) in mice and humans are the haematopoietic cells with the greatest self-renewal capacity and were shown to be CD34⁺ and CD38⁻ cell fraction within the lineage-depleted cell population (LIn⁻).^{[17] [18]} Human HSCs express the CD34 marker.^{[17] [19]} Later studies have reported that low rhodamine retention identifies LT-HSCs within the Lin⁻CD34⁺CD38⁻ population.^{[20] [21] [22]}

CD34 is expressed in roughly 20% of murine haematopoietic stem cells,^[23] and can be stimulated and reversed.^[24]

Clinical applications

CD34+ is often used clinically to quantify the number of haemopoietic stem cells for use in haemopoietic stem cell transplantation. This is generally a useful marker for cell dosing although there is some evidence that the CD34+ quantification may not be reliable in some circumstances.^[25] CD34+ cells may be isolated from blood samples using immunomagnetic techniques and used for CD34+ transplants, which have lower rates of graft-versus-host disease.^[26]

Antibodies are used to quantify and purify hematopoietic progenitor stem cells for research and for clinical bone marrow transplantation. However, counting CD34+ mononuclear cells may overestimate myeloid blasts in bone marrow smears due to hematogones (B lymphocyte precursors) and CD34+ megakaryocytes.

Cells observed as CD34+ and CD38- are of an undifferentiated, primitive form; i.e., they are multipotent hematopoietic stem cells. Thus, because of their CD34+ expression, such undifferentiated cells can be sorted out.

In tumors, CD34 is found in alveolar soft part sarcoma, preB-ALL (positive in 75%), AML (40%), AML-M7 (most), dermatofibrosarcoma protuberans, gastrointestinal stromal tumors, giant cell fibroblastoma, granulocytic sarcoma, Kaposi’s sarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, meningeal hemangiopericytomas, meningiomas, neurofibromas, schwannomas, and papillary thyroid carcinoma.

A negative CD34 may exclude Ewing's sarcoma/PNET, myofibrosarcoma of the breast, and inflammatory myofibroblastic tumors of the stomach.

Injection of CD34+ hematopoietic stem cells has been clinically applied to treat various diseases including spinal cord injury,^[27] liver cirrhosis^[28] and peripheral vascular disease.^[29]

Interactions

CD34 has been shown to interact with CRKL.^[30] It also interacts with L-selectin, important in inflammation. CD34- has been related to hair follicles' melanocyte regeneration and CD34+ with neuronal regeneration.

See also

• Cluster of differentiation
• List of histologic stains that aid in diagnosis of cutaneous conditions

Further reading

• Bellini A, Mattoli S . The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses . Laboratory Investigation; A Journal of Technical Methods and Pathology . 87 . 9 . 858–870 . September 2007 . 17607298 . 10.1038/labinvest.3700654 . free .
• Simmons DL, Satterthwaite AB, Tenen DG, Seed B . Molecular cloning of a cDNA encoding CD34, a sialomucin of human hematopoietic stem cells . Journal of Immunology . 148 . 1 . 267–271 . January 1992 . 10.4049/jimmunol.148.1.267 . 1370171 .
• Satterthwaite AB, Burn TC, Le Beau MM, Tenen DG . Structure of the gene encoding CD34, a human hematopoietic stem cell antigen . Genomics . 12 . 4 . 788–794 . April 1992 . 1374051 . 10.1016/0888-7543(92)90310-O .
• Fina L, Molgaard HV, Robertson D, Bradley NJ, Monaghan P, Delia D, Sutherland DR, Baker MA, Greaves MF . 6 . Expression of the CD34 gene in vascular endothelial cells . Blood . 75 . 12 . 2417–2426 . June 1990 . 1693532 . 10.1182/blood.V75.12.2417.2417 . free .
• Fackler MJ, Civin CI, Sutherland DR, Baker MA, May WS . Activated protein kinase C directly phosphorylates the CD34 antigen on hematopoietic cells . The Journal of Biological Chemistry . 265 . 19 . 11056–11061 . July 1990 . 1694174 . 10.1016/S0021-9258(19)38556-4 . free .
• Sutherland DR, Watt SM, Dowden G, Karhi K, Baker MA, Greaves MF, Smart JE . Structural and partial amino acid sequence analysis of the human hemopoietic progenitor cell antigen CD34 . Leukemia . 2 . 12 . 793–803 . December 1988 . 2462139 .
• Nakamura Y, Komano H, Nakauchi H . Two alternative forms of cDNA encoding CD34 . Experimental Hematology . 21 . 2 . 236–242 . February 1993 . 7678811 . .
• Huyhn A, Dommergues M, Izac B, Croisille L, Katz A, Vainchenker W, Coulombel L . Characterization of hematopoietic progenitors from human yolk sacs and embryos . Blood . 86 . 12 . 4474–4485 . December 1995 . 8541536 . 10.1182/blood.V86.12.4474.bloodjournal86124474 . free .
• Tavian M, Coulombel L, Luton D, Clemente HS, Dieterlen-Lièvre F, Péault B . Aorta-associated CD34+ hematopoietic cells in the early human embryo . Blood . 87 . 1 . 67–72 . January 1996 . 8547678 . 10.1182/blood.V87.1.67.67 . free .
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M . 6 . Generation and analysis of 280,000 human expressed sequence tags . Genome Research . 6 . 9 . 807–828 . September 1996 . 8889549 . 10.1101/gr.6.9.807 . free .
• Uchida N, Yang Z, Combs J, Pourquié O, Nguyen M, Ramanathan R, Fu J, Welply A, Chen S, Weddell G, Sharma AK, Leiby KR, Karagogeos D, Hill B, Humeau L, Stallcup WB, Hoffman R, Tsukamoto AS, Gearing DP, Péault B . 6 . The characterization, molecular cloning, and expression of a novel hematopoietic cell antigen from CD34+ human bone marrow cells . Blood . 89 . 8 . 2706–2716 . April 1997 . 9108388 . 10.1182/blood.V89.8.2706 . free .
• Ruiz ME, Cicala C, Arthos J, Kinter A, Catanzaro AT, Adelsberger J, Holmes KL, Cohen OJ, Fauci AS . 6 . Peripheral blood-derived CD34+ progenitor cells: CXC chemokine receptor 4 and CC chemokine receptor 5 expression and infection by HIV . Journal of Immunology . 161 . 8 . 4169–4176 . October 1998 . 10.4049/jimmunol.161.8.4169 . 9780190 .
• Kees UR, Ford J . Synergistic action of stem-cell factor and interleukin-7 in a human immature T-cell line . Immunology . 96 . 2 . 202–206 . February 1999 . 10233696 . 2326741 . 10.1046/j.1365-2567.1999.00674.x .
• Bistrup A, Bhakta S, Lee JK, Belov YY, Gunn MD, Zuo FR, Huang CC, Kannagi R, Rosen SD, Hemmerich S . 6 . Sulfotransferases of two specificities function in the reconstitution of high endothelial cell ligands for L-selectin . The Journal of Cell Biology . 145 . 4 . 899–910 . May 1999 . 10330415 . 2133194 . 10.1083/jcb.145.4.899 .
• Lataillade JJ, Clay D, Dupuy C, Rigal S, Jasmin C, Bourin P, Le Bousse-Kerdilès MC . Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: possible role in progenitor survival . Blood . 95 . 3 . 756–768 . February 2000 . 10648383 . 10.1182/blood.V95.3.756 .
• Felschow DM, McVeigh ML, Hoehn GT, Civin CI, Fackler MJ . The adapter protein CrkL associates with CD34 . Blood . 97 . 12 . 3768–3775 . June 2001 . 11389015 . 10.1182/blood.V97.12.3768 . free .
• Dobo I, Robillard N, Pineau D, Geneviève F, Piard N, Rapp MJ, Boasson M, Zandecki M, Hermouet S . 6 . Use of pathology-specific peripheral blood CD34 thresholds to predict leukapheresis CD34 content with optimal accuracy: a bicentric analysis of 299 leukaphereses . Annals of Hematology . 80 . 11 . 639–646 . November 2001 . 11757722 . 10.1007/s002770100365 . 23018429 .
• Hogan CJ, Shpall EJ, Keller G . Differential long-term and multilineage engraftment potential from subfractions of human CD34+ cord blood cells transplanted into NOD/SCID mice . Proceedings of the National Academy of Sciences of the United States of America . 99 . 1 . 413–418 . January 2002 . 11782553 . 117574 . 10.1073/pnas.012336799 . . 2002PNAS...99..413H . 3057551 . free .
• Krauter J, Hartl M, Hambach L, Kohlenberg A, Gunsilius E, Ganser A, Heil G . Receptor-mediated endocytosis of CD34 on hematopoietic cells after stimulation with the monoclonal antibody anti-HPCA-1 . Journal of Hematotherapy & Stem Cell Research . 10 . 6 . 863–871 . December 2001 . 11798512 . 10.1089/152581601317210953 .
• Okuno Y, Iwasaki H, Huettner CS, Radomska HS, Gonzalez DA, Tenen DG, Akashi K . Differential regulation of the human and murine CD34 genes in hematopoietic stem cells . Proceedings of the National Academy of Sciences of the United States of America . 99 . 9 . 6246–6251 . April 2002 . 11983914 . 122934 . 10.1073/pnas.092027799 . free . 2002PNAS...99.6246O . 3058657 .
• Hotfilder M, Röttgers S, Rosemann A, Jürgens H, Harbott J, Vormoor J . Immature CD34+CD19- progenitor/stem cells in TEL/AML1-positive acute lymphoblastic leukemia are genetically and functionally normal . Blood . 100 . 2 . 640–646 . July 2002 . 12091359 . 10.1182/blood.V100.2.640 . free .

External links

• • Mouse CD Antigen Chart
• Human CD Antigen Chart

Notes and References

1. Web site: Entrez Gene: CD34 CD34 molecule.
2. Simmons DL, Satterthwaite AB, Tenen DG, Seed B . Molecular cloning of a cDNA encoding CD34, a sialomucin of human hematopoietic stem cells . Journal of Immunology . 148 . 1 . 267–271 . January 1992 . 10.4049/jimmunol.148.1.267 . 1370171 .
3. Satterthwaite AB, Burn TC, Le Beau MM, Tenen DG . Structure of the gene encoding CD34, a human hematopoietic stem cell antigen . Genomics . 12 . 4 . 788–794 . April 1992 . 1374051 . 10.1016/0888-7543(92)90310-O .
4. Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH . Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells . Journal of Immunology . 133 . 1 . 157–165 . July 1984 . 10.4049/jimmunol.133.1.157 . 6586833 .
5. Tindle RW, Nichols RA, Chan L, Campana D, Catovsky D, Birnie GD . A novel monoclonal antibody BI-3C5 recognises myeloblasts and non-B non-T lymphoblasts in acute leukaemias and CGL blast crises, and reacts with immature cells in normal bone marrow . Leukemia Research . 9 . 1 . 1–9 . 1985 . 3857402 . 10.1016/0145-2126(85)90016-5 .
6. Tindle RW. Katz F. Martin H. Watt D. Catovsky D. Janossy G. Greaves M.. 1987. BI-3C5 (CD34) defines multipotential and lineage restricted progenitor cells and their leukaemic counterparts .. In 'Leucocyte Typing 111: White Cell Differentiation Antigens. Oxford University Press, 654-655.
7. Loken M. Shah V. Civin CI... 1987. Characterization of myeloid antigens on human bone marrow using multicolour immunofluorescence. In: McMichael, Leucocyte Typing III:White Cell Differentiation Antigens.Oxford University Press 630-635.
8. Nielsen JS, McNagny KM . Novel functions of the CD34 family . Journal of Cell Science . 121 . Pt 22 . 3683–3692 . November 2008 . 18987355 . 10.1242/jcs.037507 . 18154561 .
9. Furness SG, McNagny K . Beyond mere markers: functions for CD34 family of sialomucins in hematopoiesis . Immunologic Research . 34 . 1 . 13–32 . 2006 . 16720896 . 10.1385/IR:34:1:13 . 41420678 .
10. Berg EL, Mullowney AT, Andrew DP, Goldberg JE, Butcher EC . Complexity and differential expression of carbohydrate epitopes associated with L-selectin recognition of high endothelial venules . The American Journal of Pathology . 152 . 2 . 469–477 . February 1998 . 9466573 . 1857953 .
11. Suzawa K, Kobayashi M, Sakai Y, Hoshino H, Watanabe M, Harada O, Ohtani H, Fukuda M, Nakayama J . 6 . Preferential induction of peripheral lymph node addressin on high endothelial venule-like vessels in the active phase of ulcerative colitis . The American Journal of Gastroenterology . 102 . 7 . 1499–1509 . July 2007 . 17459027 . 10.1111/j.1572-0241.2007.01189.x . 7630223 .
12. Drew E, Merzaban JS, Seo W, Ziltener HJ, McNagny KM . CD34 and CD43 inhibit mast cell adhesion and are required for optimal mast cell reconstitution . Immunity . 22 . 1 . 43–57 . January 2005 . 15664158 . 10.1016/j.immuni.2004.11.014 . free .
13. Strilić B, Kucera T, Eglinger J, Hughes MR, McNagny KM, Tsukita S, Dejana E, Ferrara N, Lammert E . 6 . The molecular basis of vascular lumen formation in the developing mouse aorta . Developmental Cell . 17 . 4 . 505–515 . October 2009 . 19853564 . 10.1016/j.devcel.2009.08.011 . free .
14. Blanchet MR, Maltby S, Haddon DJ, Merkens H, Zbytnuik L, McNagny KM . CD34 facilitates the development of allergic asthma . Blood . 110 . 6 . 2005–2012 . September 2007 . 17557898 . 10.1182/blood-2006-12-062448 . 10999494 .
15. Blanchet MR, Bennett JL, Gold MJ, Levantini E, Tenen DG, Girard M, Cormier Y, McNagny KM . 6 . CD34 is required for dendritic cell trafficking and pathology in murine hypersensitivity pneumonitis . American Journal of Respiratory and Critical Care Medicine . 184 . 6 . 687–698 . September 2011 . 21642249 . 3208601 . 10.1164/rccm.201011-1764OC .
16. Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A . Concise review: evidence for CD34 as a common marker for diverse progenitors . Stem Cells . 32 . 6 . 1380–1389 . June 2014 . 24497003 . 4260088 . 10.1002/stem.1661 .
17. Ramsfjell V, Bryder D, Björgvinsdóttir H, Kornfält S, Nilsson L, Borge OJ, Jacobsen SE . Distinct requirements for optimal growth and In vitro expansion of human CD34(+)CD38(-) bone marrow long-term culture-initiating cells (LTC-IC), extended LTC-IC, and murine in vivo long-term reconstituting stem cells . Blood . 94 . 12 . 4093–4102 . December 1999 . 10.1182/blood.V94.12.4093 . 10590054 .
18. Hogan CJ, Shpall EJ, Keller G . Differential long-term and multilineage engraftment potential from subfractions of human CD34+ cord blood cells transplanted into NOD/SCID mice . Proceedings of the National Academy of Sciences of the United States of America . 99 . 1 . 413–418 . January 2002 . 11782553 . 10.1073/pnas.012336799 . 117574 . 2002PNAS...99..413H . free .
19. Ebihara Y, Wada M, Ueda T, Xu MJ, Manabe A, Tanaka R, Ito M, Mugishima H, Asano S, Nakahata T, Tsuji K . 6 . Reconstitution of human haematopoiesis in non-obese diabetic/severe combined immunodeficient mice by clonal cells expanded from single CD34+CD38- cells expressing Flk2/Flt3 . British Journal of Haematology . 119 . 2 . 525–534 . November 2002 . 12406096 . 10.1046/j.1365-2141.2002.03820.x . 10040999 . free .
20. McKenzie JL, Takenaka K, Gan OI, Doedens M, Dick JE . Low rhodamine 123 retention identifies long-term human hematopoietic stem cells within the Lin-CD34+CD38- population . Blood . 109 . 2 . 543–545 . January 2007 . 16990597 . 10.1182/blood-2006-06-030270 . 25804835 . free .
21. Wolf NS, Koné A, Priestley GV, Bartelmez SH . In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection . Experimental Hematology . 21 . 5 . 614–622 . May 1993 . 8513861 .
22. Chen CZ, Li L, Li M, Lodish HF . The endoglin(positive) sca-1(positive) rhodamine(low) phenotype defines a near-homogeneous population of long-term repopulating hematopoietic stem cells . Immunity . 19 . 4 . 525–533 . October 2003 . 14563317 . 10.1016/s1074-7613(03)00265-6 . free .
23. Ogawa M, Tajima F, Ito T, Sato T, Laver JH, Deguchi T . CD34 expression by murine hematopoietic stem cells. Developmental changes and kinetic alterations . Annals of the New York Academy of Sciences . 938 . 139–145 . June 2001 . 1 . 11458501 . 10.1111/j.1749-6632.2001.tb03583.x . 83284239 . 2001NYASA.938..139O .
24. Tajima F, Sato T, Laver JH, Ogawa M . CD34 expression by murine hematopoietic stem cells mobilized by granulocyte colony-stimulating factor . Blood . 96 . 5 . 1989–1993 . September 2000 . 10961905 . 10.1182/blood.V96.5.1989 .
25. Hua P, Roy N, de la Fuente J, Wang G, Thongjuea S, Clark K, Roy A, Psaila B, Ashley N, Harrington Y, Nerlov C, Watt SM, Roberts I, Davies JO . 6 . Single-cell analysis of bone marrow-derived CD34+ cells from children with sickle cell disease and thalassemia . Blood . 134 . 23 . 2111–2115 . December 2019 . 31697810 . 7259822 . 10.1182/blood.2019002301 . free .
26. Tamari R, Oran B, Hilden P, Maloy M, Kongtim P, Papadopoulos EB, Rondon G, Jakubowski AA, Andersson BS, Devlin SM, Ahmed S, Popat UR, Ponce D, Chen J, Sauter C, Young JW, de Lima M, Perales MA, O'Reilly RJ, Giralt SA, Champlin RE, Castro-Malaspina H . 6 . Allogeneic Stem Cell Transplantation for Advanced Myelodysplastic Syndrome: Comparison of Outcomes between CD34⁺ Selected and Unmodified Hematopoietic Stem Cell Transplantation . Biology of Blood and Marrow Transplantation . 24 . 5 . 1079–1087 . May 2018 . 29325829 . 6529210 . 10.1016/j.bbmt.2018.01.001 .
27. Srivastava A, Bapat M, Ranade S, Srinivasan V, Murugan P, Manjunath S, Thamaraikannan P, Abraham S . Autologous Multiple Injections of in Vitro Expanded Autologous Bone Marrow Stem Cells For Cervical Level Spinal Cord Injury - A Case Report . Journal of Stem Cells and Regenerative Medicine . 2010 .
28. Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I . 6 . Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy . Stem Cells . 24 . 10 . 2292–2298 . October 2006 . 16778155 . 10.1634/stemcells.2005-0542 . 5649484 .
29. Subrammaniyan R, Amalorpavanathan J, Shankar R, Rajkumar M, Baskar S, Manjunath SR, Senthilkumar R, Murugan P, Srinivasan VR, Abraham S . 6 . Application of autologous bone marrow mononuclear cells in six patients with advanced chronic critical limb ischemia as a result of diabetes: our experience . Cytotherapy . 13 . 8 . 993–999 . September 2011 . 21671823 . 10.3109/14653249.2011.579961 . 27251276 .
30. Felschow DM, McVeigh ML, Hoehn GT, Civin CI, Fackler MJ . The adapter protein CrkL associates with CD34 . Blood . 97 . 12 . 3768–3775 . June 2001 . 11389015 . 10.1182/blood.V97.12.3768 . free .